This invention relates to a method for the prophylaxis of or reducing the severity of post respiratory viral infection in the respiratory tract by bacteria by administering a PDE 4-specific inhibitor prior to or during the course of a viral infection or thereafter during the course of the bacterial infection.
Primary respiratory tract viral infections have been shown to lead to increased susceptibility to secondary bacterial infections [Loosli C. G. 1973, Med. 52, 369-384; Stuart-Harris C. H., Laird J., Tyrell D. A., Kelsall M. H., Franks Z. C., Pownall M. 1949, J. Hyg. 47; 434; and Stuart-Harris C. H. 1966, Brit. Med. J. 149; 217]. The mechanisms of this susceptibility are poorly understood. And there is no prophylactics or treatments available for reducing or moderating this susceptibility. Herein there is provided a model for studying this phenomenon and a demonstrated method for reducing this susceptibility by administering a PDE 4 specific inhibitor.
Streptococcus pneumoniae is regarded as one of the most common causes of community-acquired pneumonia and is an important cause of illness and death in industrialized countries. S. pneumoniae colonizes the human nasophararynx and in some circumstances the organisms spread to cause upper or lower respiratory tract infection. The mechanisms underlying the transition from a benign colonization to disease are not well understood. A number of mechanisms have been proposed but the nature of this transition remains to be discovered.
Epidemiological studies have demonstrated that viral infections pre-dispose the host lung to bacterial pneumonia and secondary bacterial pneumonia is the most frequent complication of influenza infection in man [Loosli C. G. 1973, Med. 52, 369-384; Stuart-Harris C. H., Laird J., Tyrell D. A., Kelsall M. H., Franks Z. C., Pownall M. 1949, J. Hyg. 47; 434; and Stuart-Harris C. H. 1966, Brit. Med. J. 149; 217]. Investigators have demonstrated in vitro that cells stimulated with either cytokines or virus show enhanced bacterial adherence and that bacterial adherence to host tissues is an essential step in bacterial colonization and infections [Jones W. T., Menna J. H. 1982, Infect. Immun. 38; 791-794; Jiang Z., Nagata N., Molina E., Bakaletz L. O., Hawkins H., Patel J. A. 1999, Infect. Immun. 67; 187-192; Sanford B. A., Shelokov A., Ramsay M. A. 1978, J. Infect. Dis. 137; 176-181; Geelen S., Bhattacharyya C., Tuomanen E. 1993, Infect. Immun. 61; 1538-1543; and Hakansson A., Kidd A., Wadell G., Sabharwal H., Svanborg C. 1994, Infect. Immun. 62, 2707-2714.]
Phase variation of pneumococci has been demonstrated to be one of the virulence mechanisms of respiratory tract infections. For S. pneumoniae the transparent phenotype has been shown to adhere to lung epithelial cells and to be more virulent in an infant rat colonization model than the opaque phenotype [Kim J. O., Weiser J. N. 1998, J. Infect. Dis. 177:368-377; and Weiser J. N., Austrian R., Sreenivasan P. K., Masure H. R. 1994, Infect. Immun. 62; 2582-2589]. The mechanism of the altered virulence of S. pneumoniae phenotypes has been shown to be linked to the cell wall and the production of the capsular glycoprotein CbpA [Berube L. R., et al, 1999, Micro. Path. 26; 65-75 and Geelen S. et al, 1993, Infect. Immun., 61; 1538-1543].
Here-in there is described a murine model of sub-lethal influenza infection followed by Streptococcus pneumoniae co-infection. Also disclosed is the finding that administrating a PDE 4-specific inhibitor reduces the susceptibility of a mammal to post-viral bacterial infection.
This invention relates to a means for reducing the severity of or preventing a bacterial infection of the respiratiory tract following a respiratory viral tract infection by administering an effective amount of a PDE 4-specific inhibitor alone or in combination with a pharmaceutically acceptable excipient prior to or during the course of the viral infection, during the course of both the viral infection and the bacterial infection following thereafter, or during the course of the bacterial infection alone.